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1.
Eur Heart J ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31424503

RESUMO

AIMS: Although loop diuretics are widely used to treat heart failure (HF), there is scarce contemporary data to guide diuretic adjustments in the outpatient setting. METHODS AND RESULTS: In a prospective, randomized and double-blind protocol, we tested the safety and tolerability of withdrawing low-dose furosemide in stable HF outpatients at 11 HF clinics in Brazil. The trial had two blindly adjudicated co-primary outcomes: (i) symptoms assessment quantified as the area under the curve (AUC) of a dyspnoea score on a visual-analogue scale evaluated at 4 time-points (baseline, Day 15, Day 45, and Day 90) and (ii) the proportion of patients maintained without diuretic reuse during follow-up. We enrolled 188 patients (25% females; 59 ± 13 years old; left ventricular ejection fraction = 32 ± 8%) that were randomized to furosemide withdrawal (n = 95) or maintenance (n = 93). For the first co-primary endpoint, no significant difference in patients' assessment of dyspnoea was observed in the comparison of furosemide withdrawal with continuous administration [median AUC 1875 (interquartile range, IQR 383-3360) and 1541 (IQR 474-3124), respectively; P = 0.94]. For the second co-primary endpoint, 70 patients (75.3%) in the withdrawal group and 77 patients (83.7%) in the maintenance group were free of furosemide reuse during follow-up (odds ratio for additional furosemide use with withdrawal 1.69, 95% confidence interval 0.82-3.49; P = 0.16). Heart failure-related events (hospitalizations, emergency room visits, and deaths) were infrequent and similar between groups (P = 1.0). CONCLUSIONS: Diuretic withdrawal did not result in neither increased self-perception of dyspnoea nor increased need of furosemide reuse. Diuretic discontinuation may deserve consideration in stable outpatients with no signs of fluid retention receiving optimal medical therapy. CLINICALTRIALS.GOV IDENTIFIER: NCT02689180.

2.
Am Heart J ; 194: 125-131, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29223430

RESUMO

AIMS: Furosemide is commonly prescribed for symptom relief in heart failure (HF) patients. Although few data support the continuous use of loop diuretics in apparently euvolemic HF patients with mild symptoms, there is concern about safety of diuretic withdrawal in these patients. The ReBIC-1 trial was designed to evaluate the safety and tolerability of withdrawing furosemide in stable, euvolemic, chronic HF outpatients. This multicenter initiative is part of the Brazilian Research Network in Heart Failure (ReBIC) created to develop clinical studies in HF and composed predominantly by university tertiary care hospitals. METHODS: The ReBIC-1 trial is currently enrolling HF patients in NYHA functional class I-II, left ventricular ejection fraction ≤45%, without a HF-related hospital admission within the last 6 months, receiving a stable dose of furosemide (40 or 80 mg per day) for at least 6 months. Eligible patients will be randomized to maintain or withdraw furosemide in a double-blinded protocol. The trial has two co-primary outcomes: (1) dyspnea assessment using a visual-analogue scale evaluated at 4 time points and (2) the proportion of patients maintained without diuretics during the follow-up period. Total sample size was calculated to be 220 patients. Enrolled patients will be followed up to 90 days after randomization, and diuretic will be restarted if clinical deterioration or signs of congestion are detected. Pre-defined sub-group analysis based on NT-proBNP levels at baseline is planned. PERSPECTIVE: Evidence-based strategies aiming to simplify HF pharmacotherapy are needed in clinical practice. The ReBIC-1 trial will determine the safety of withdrawing furosemide in stable chronic HF patients.


Assuntos
Tolerância a Medicamentos , Furosemida/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Pacientes Ambulatoriais , Idoso , Biomarcadores/sangue , Deterioração Clínica , Diuréticos/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Resultado do Tratamento
3.
Artigo em Inglês | MEDLINE | ID: mdl-28299921

RESUMO

BACKGROUND: Patients with primary microvascular angina (PMA) commonly exhibit abnormal left ventricular function (LVF) during exercise, potentially owing to myocardial ischemia. Herein, we investigated n PMA patients the effect of the reduction of myocardial perfusion disorders, by using aerobic physical training, upon LVF response to exercise. METHODS: Overall, 15 patients (mean age, 53.7±8.9 years) with PMA and 15 healthy controls (mean age, 51.0±9.4 years) were studied. All subjects were subjected to baseline resting and exercise ventriculography, myocardial perfusion scintigraphy (MPS), and cardiopulmonary testing. PMA group members then participated in a 4-month physical training program and were reevaluated via the same methods applied at baseline. RESULTS: Baseline left ventricular ejection fraction (LVEF) determinations by ventriculography were similar for both groups (PMA, 67.7±10.2%; controls, 66.5±5.4%; p=0.67). However, a significant rise in LVEF seen in control subjects during exercise (75.3±6.2%; p=0.0001) did not materialize during peak exercise in patients with PMA (67.7±10.2%; p=0.47). Of the 12 patients in the PMA group who completed the training program, 10 showed a significant reduction in reversible perfusion defects during MPS. Nevertheless, LVEF at rest (63.5±8.7%) and at peak exercise (67.3±15.9%) did not differ significantly (p=0.30) in this subset. CONCLUSIONS: In patients with PMA, reduced left ventricular inotropic reserve observed during exercise did not normalize after improving myocardial perfusion through aerobic physical training.

4.
Mayo Clin Proc ; 92(3): 460-466, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28259231

RESUMO

The World Health Organization considers the Zika virus (ZIKV) outbreak in the Americas a global public health emergency. The neurologic complications due to ZIKV infection comprise microcephaly, meningoencephalitis, and Guillain-Barré syndrome. We describe a fatal case of an adult patient receiving an immunosuppressive regimen following heart transplant. The patient was admitted with acute neurologic impairment and experienced progressive hemodynamic instability and mental deterioration that finally culminated in death. At autopsy, a pseudotumoral form of ZIKV meningoencephalitis was confirmed. Zika virus infection was documented by reverse trancriptase-polymerase chain reaction, immunohistochemistry, and immunofluorescence and electron microscopy of the brain parenchyma and cerebral spinal fluid. The sequencing of the viral genome in this patient confirmed a Brazilian ZIKV strain. In this case, central nervous system involvement and ZIKV propagation to other organs in a disseminated pattern is quite similar to that observed in other fatal Flaviviridae viral infections.


Assuntos
Transplante de Coração/efeitos adversos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Meningoencefalite/virologia , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Doença Aguda , Adulto , Líquido Cefalorraquidiano/virologia , Evolução Fatal , Imunofluorescência/métodos , Genoma Viral , Humanos , Imuno-Histoquímica , Imunossupressores/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Meningoencefalite/diagnóstico por imagem , Meningoencefalite/imunologia , Neuroimagem , Tecido Parenquimatoso/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Zika virus/genética , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/imunologia
5.
Exp Toxicol Pathol ; 69(4): 213-219, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28153388

RESUMO

OBJECTIVES: Doxorubicin (DXR), an anthracyclic antineoplastic agent, is one of the most commonly drug utilized to induce dilated cardiomyopathy (DCM) and heart failure (HF), but the well optimized protocol for cardiomyopathy induction leading to development of cardiac systolic dysfunction is unclear. This study aims to critically compare short-term and long-term DXR injection protocols for the induction of DCM in rats. METHODS: Animals were allocated into 3 experimental groups: a ST (short-term DXR injection) group, in which animals received 6 intraperitoneal (i.p.) injections of DXR (2.5mg/kg per dose) over a period of 2 weeks (cumulative dose of 15mg/kg); a LT (long-term DXR injection) group in which animals received weekly i.p. injections of DXR (2mg/kg per dose) over a period of 9 weeks (cumulative dose of 18mg/kg); and a control group in which animals received an appropriate volume of 0.9% saline i.p. All animals were submitted to echocardiography analysis at baseline and after completion treatment. Afterwards, the hearts were collected for conventional light microscopy and collagen quantification. RESULTS: Morphological myocardial analysis of both DXR-treated groups showed an identical pattern of swollen and vacuolated cardiomyocytes and disorganization of myofibrils. There was pronounced interstitial fibrosis in both groups of DXR-treated hearts as compared to controls, as assessed by the interstitial collagen volume fraction. There was no difference in interstitial fibrosis between the ST and LT groups. The echocardiography analysis of the LT group showed structural and functional findings compatible with DCM, including increased left ventricular systolic (5.02±0.96mm) and diastolic (7.68±0.96mm) dimensions and reduction of ejection fraction (69.40±8.51%) as compared to the ST group (4.10±0.89mm, 7.32±0.84, and 79.68±7.23%, respectively) and control group (4.07±0.72mm, 7.17±0.68mm and 80.08±4.71%, respectively), ANOVA p<0.01. CONCLUSIONS: These results indicate that LT injection of DXR is more effective than ST injection in inducing left ventricular dysfunction and structural cardiac changes resembling those found in dilated cardiomyopathy.


Assuntos
Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Modelos Animais de Doenças , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/administração & dosagem , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar
6.
Auton Neurosci ; 193: 97-103, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26471065

RESUMO

Hypertension is often accompanied by autonomic dysfunction, which is detrimental to cardiac regulation. On the other hand, cholinergic stimulation through inhibition of acetylcholinesterase appears to have beneficial effects on cardiac autonomic control. Thus, our objective was to investigate the effects of chronic cholinergic stimulation on hemodynamic and cardiovascular autonomic control parameters in spontaneously hypertensive rats (SHR). For this, 26-week-old SHR (N = 32) and Wistar Kyoto rats (WK; N = 32) were divided into two groups: one treated with vehicle (H2O; N = 16) and the other treated with pyridostigmine bromide (PYR; N = 16) in drinking water (25 mg/kg/day) for 2 weeks. All groups were subjected to recording of arterial pressure (AP) and heart rate (HR), quantification of ejection fraction (EF), evaluation of cardiac tonic autonomic balance by means of double autonomic blockade with methylatropine and propranolol, analysis of systolic AP (SAP) and HR variability (HRV), and evaluation of baroreflex sensitivity (BRS). AP, HR, and EF were reduced in the SHR-PYR group compared with the SHR-H2O group. Evaluation of autonomic parameters revealed an increase in vagal tone participation in cardiac tonic autonomic balance and reduced SAP variability; however, no changes were observed in HRV or BRS. These results suggest that chronic cholinergic stimulation with pyridostigmine bromide promotes reduction in the hemodynamic parameters AP, HR, and EF. Additionally, tonic autonomic balance was improved and a reduction in LF oscillations of SAP variability was observed that could not be attributed to BRS, as the latter did not change. Further studies should be conducted to identify the mechanisms involved in the observed responses.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Volume Sistólico/fisiologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Masculino , Brometo de Piridostigmina/farmacologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Volume Sistólico/efeitos dos fármacos , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiopatologia
7.
Eur J Pharmacol ; 670(2-3): 541-53, 2011 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-21946105

RESUMO

The critical importance of dystrophin to cardiomyocyte contraction and sarcolemmal and myofibers integrity, led us to test the hypothesis that dystrophin reduction/loss could be involved in the pathogenesis of doxorubicin-induced cardiomyopathy, in order to determine a possible specific structural culprit behind heart failure. Rats received total cumulative doses of doxorubicin during 2 weeks: 3.75, 7.5, and 15 mg/kg. Controls rats received saline. Fourteen days after the last injection, hearts were collected for light and electron microscopy, immunofluorescence and western blot. The cardiac function was evaluated 7 and 14 days after drug or saline. Additionally, dantrolene (5 mg/kg), a calcium-blocking agent that binds to cardiac ryanodine receptors, was administered to controls and doxorubicin-treated rats (15 mg/kg). This study offers novel and mechanistic data to clarify molecular events that occur in the myocardium in doxorubicin-induced chronic cardiomyopathy. Doxorubicin led to a marked reduction/loss in dystrophin membrane localization in cardiomyocytes and left ventricular dysfunction, which might constitute, in association with sarcomeric actin/myosin proteins disruption, the structural basis of doxorubicin-induced cardiac depression. Moreover, increased sarcolemmal permeability suggests functional impairment of the dystrophin-glycoprotein complex in cardiac myofibers and/or oxidative damage. Increased expression of calpain, a calcium-dependent protease, was markedly increased in cardiomyocytes of doxorubicin-treated rats. Dantrolene improved survival rate and preserved myocardial dystrophin, calpain levels and cardiac function, which supports the opinion that calpain mediates dystrophin loss and myofibrils degradation in doxorubicin-treated rats. Studies are needed to further elucidate this mechanism, mainly regarding specific calpain inhibitors, which may provide new interventional pathways to prevent doxorubicin-induced cardiomyopathy.


Assuntos
Calpaína/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Doxorrubicina/efeitos adversos , Distrofina/metabolismo , Actinas/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Dantroleno/farmacologia , Eletrocardiografia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Miosinas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Sarcolema/efeitos dos fármacos , Sarcolema/metabolismo , Análise de Sobrevida , Fatores de Tempo
8.
Rev. bras. cardiol. invasiva ; 17(3): 358-368, jul.-set. 2009. ilus, tab
Artigo em Português | LILACS | ID: lil-535096

RESUMO

A alteração regional da mobilidade segmentar do ventrículo esquerdo é marcador precoce de miocardiopatia chagásica crônica. Demonstramos recentemente que a discinergia em algumas regiões ventriculares pode ser revertida pela potenciação pós-extrassistólica. Apesar de angiografia coronária normal, pacientes com miocardiopatia chagásica apresentam falhas de perfusão, corroborando a hipótese de que a hibernação miocárdica pode ser responsável pelas anormalidades de mobilidade segmentar revertidas durante a potenciação pós-extrassistólica. Método: Vinte e dois pacientes consecutivos portadores de miocardiopatia chagásica foram submetidos a angiografia coronária, ventriculografia e cintilografia miocárdica com tálio-201 com o protocolo estresse-redistribuição-reinjeção para avaliação da perfusão dos segmentos do ventrículo esquerdo...


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doença de Chagas/fisiopatologia , Estimulação Elétrica/métodos , Contração Miocárdica
9.
JACC Cardiovasc Imaging ; 2(2): 164-72, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19356551

RESUMO

OBJECTIVES: This study aimed at analyzing the association between myocardial perfusion changes and the progression of left ventricular systolic dysfunction in patients with chronic Chagas' cardiomyopathy (CCC). BACKGROUND: Pathological and experimental studies have suggested that coronary microvascular derangement, and consequent myocardial perfusion disturbance, may cause myocardial damage in CCC. METHODS: Patients with CCC (n = 36, ages 57 +/- 10 years, 17 males), previously having undergone myocardial perfusion single-positron emission computed tomography and 2-dimensional echocardiography, prospectively underwent a new evaluation after an interval of 5.6 +/- 1.5 years. Stress and rest myocardial perfusion defects were quantified using polar maps and normal database comparison. RESULTS: Between the first and final evaluations, a significant reduction of left ventricular ejection fraction was observed (55 +/- 11% and 50 +/- 13%, respectively; p = 0.0001), as well as an increase in the area of the perfusion defect at rest (18.8 +/- 14.1% and 26.5 +/- 19.1%, respectively; p = 0.0075). The individual increase in the perfusion defect area at rest was significantly correlated with the reduction in left ventricular ejection fraction (R = 0.4211, p = 0.0105). Twenty patients with normal coronary arteries (56%) showed reversible perfusion defects involving 10.2 +/- 9.7% of the left ventricle. A significant topographic correlation was found between reversible defects and the appearance of new rest perfusion defects at the final evaluation. Of the 47 segments presenting reversible perfusion defects in the initial study, 32 (68%) progressed to perfusion defects at rest, and of the 469 segments not showing reversibility in the initial study, only 41 (8.7%) had the same progression (p < 0.0001, Fisher exact test). CONCLUSIONS: In CCC patients, the progression of left ventricular systolic dysfunction was associated with both the presence of reversible perfusion defects and the increase in perfusion defects at rest. These results support the notion that myocardial perfusion disturbances participate in the pathogenesis of myocardial injury in CCC.


Assuntos
Cardiomiopatia Chagásica/fisiopatologia , Circulação Coronária , Sístole , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Idoso , Cardiomiopatia Chagásica/complicações , Cardiomiopatia Chagásica/patologia , Progressão da Doença , Ecocardiografia , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio , Volume Sistólico , Tomografia Computadorizada de Emissão de Fóton Único , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
10.
Rev. bras. cardiol. invasiva ; 15(2): 107-114, abr.-jun. 2007. ilus, tab
Artigo em Português | LILACS | ID: lil-452009

RESUMO

Introdução: A persistência transitória de defeitos perfusionais imediatamente após intervenção coronária percutânea bem sucedida para correção de estenoses coronárias é bem documentada. Método: Para testar a hipótese de que tais anormalidades perfisionais sejam associadas a distúrbios microcirculatórios causados por microembolização coronária, comparaou-se a intensidade e extensão desses defeitos perfusionais detectados com cintilografia miocárdica em grupos randomicamente constituídos de pacientes tratados com angioplastia coronária por balão (AB) ou submetidos a aterectomia rotacional complementada por balão (AR mais B). As características clínicas e angiográficas foram comparáveis nos dois grupos, assim como o sucesso do procedimento de angioplastia coronária....


Assuntos
Humanos , Masculino , Feminino , Adulto , Angioplastia Coronária com Balão/métodos , Angioplastia Coronária com Balão , Aterectomia Coronária/métodos , Aterectomia Coronária , Microcirculação/anormalidades
11.
Circulation ; 115(9): 1109-23, 2007 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-17339569

RESUMO

BACKGROUND: Chagas disease remains a significant public health issue and a major cause of morbidity and mortality in Latin America. Despite nearly 1 century of research, the pathogenesis of chronic Chagas cardiomyopathy is incompletely understood, the most intriguing challenge of which is the complex host-parasite interaction. METHODS AND RESULTS: A systematic review of the literature found in MEDLINE, EMBASE, BIREME, LILACS, and SCIELO was performed to search for relevant references on pathogenesis and pathophysiology of Chagas disease. Evidence from studies in animal models and in anima nobile points to 4 main pathogenetic mechanisms to explain the development of chronic Chagas heart disease: autonomic nervous system derangements, microvascular disturbances, parasite-dependent myocardial aggression, and immune-mediated myocardial injury. Despite its prominent peculiarities, the role of autonomic derangements and microcirculatory disturbances is probably ancillary among causes of chronic myocardial damage. The pathogenesis of chronic Chagas heart disease is dependent on a low-grade but incessant systemic infection with documented immune-adverse reaction. Parasite persistence and immunological mechanisms are inextricably related in the myocardial aggression in the chronic phase of Chagas heart disease. CONCLUSIONS: Most clinical studies have been performed in very small number of patients. Future research should explore the clinical potential implications and therapeutic opportunities of these 2 fundamental underlying pathogenetic mechanisms.


Assuntos
Cardiomiopatia Chagásica/etiologia , Animais , Anticorpos Antiprotozoários/imunologia , Autoimunidade , Sistema Nervoso Autônomo/fisiopatologia , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/fisiopatologia , Cricetinae , Morte Súbita Cardíaca/etiologia , Denervação , Coração/parasitologia , Sistema de Condução Cardíaco/fisiopatologia , Interações Hospedeiro-Parasita , Humanos , Camundongos , Microcirculação , Modelos Animais , Modelos Cardiovasculares , Modelos Neurológicos , Mimetismo Molecular , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/fisiopatologia , Miocardite/etiologia , Miocardite/parasitologia , Miocárdio/imunologia , Miocárdio/patologia , Nitroimidazóis/uso terapêutico , Sistema Nervoso Parassimpático/fisiopatologia , Subpopulações de Linfócitos T/imunologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/fisiologia , Vacinação , Disfunção Ventricular Esquerda/etiologia
12.
Int J Cardiol ; 116(1): 98-106, 2007 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-16828898

RESUMO

BACKGROUND: Scorpion envenomation (SE) may present severe cardiac dysfunction with acute pulmonary edema and cardiogenic shock. The pathophysiology of this acute heart failure is still controversial. We aimed at assessing the contribution of the myocardial ischemia to the left ventricular dysfunction in SE by using 99mTc-Sestamibi myocardial perfusion scintigraphy (MPS). METHODS: Twelve children (7 males, 1-12 years old) presenting severe Tityus serrulatus envenomation were prospectively submitted to MPS within 72 h (acute) and 15 days (follow-up) after the event. MPS images were interpreted using a visual semi-quantitative uptake score (0 = normal, 4 = absent). Echocardiography was used for the assessment of left ventricular (LV) ejection fraction (EF) and regional wall motion (WM) by using a semi-quantitative score (0 = normal, 4 = akinesia). A 16-segment LV model was used. RESULTS: Initial echocardiography showed marked WM abnormalities with a mean score of 31.4+/-13.9, and a reduced EF (36+/-16%). All patients exhibited myocardial perfusion (MP) defects. The mean MP uptake score was 14.6+/-7.8. A significant topographic association between MP and WM changes was obtained (p<0.0001, Fischer exact test). A positive correlation was obtained between the summed WM and MP scores (R=0.68, p=0.016). Follow-up evaluation showed a significant improvement of LVEF (65+/-10%) and WM score (3.9+/-4.2), parallel to the normalization of MP. CONCLUSIONS: These observations strongly support the participation of transitory myocardial ischemia in the mechanism of the acute cardiac dysfunction caused by severe scorpion envenoming. Micro vascular spasm related to the catecholamine over stimulation may be the pathophysiologic link triggering the myocardial perfusion disturbance in this syndrome.


Assuntos
Isquemia Miocárdica/induzido quimicamente , Venenos de Escorpião/envenenamento , Picaduras de Aranhas/complicações , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/fisiopatologia , Doença Aguda , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Isquemia Miocárdica/diagnóstico por imagem , Estudos Prospectivos , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/terapia , Cintilografia , Resultado do Tratamento , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/terapia
13.
J Nucl Med ; 46(1): 98-105, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15632039

RESUMO

UNLABELLED: Reporter gene imaging holds promise for noninvasive monitoring of cardiac gene therapy. We recently demonstrated that (124)I-labeled 2'-fluoro-2'-deoxy-5'-iodo-1beta-d-arabinofuranosyluracil ((124)I-FIAU) is suitable for PET of myocardial expression of herpes simplex virus type 1 thymidine kinase reporter gene (HSV1-tk). In contrast to previous studies in tumors, early specific uptake was followed by rapid washout. Myocardial kinetics of (124)I-FIAU are still poorly understood. This study aimed at a further investigation under controlled conditions using an isolated heart perfusion model. METHODS: Male Wistar rats underwent transthoracic regional injection of replication-defective adenovirus (2.5 x 10(9) plaque-forming units) containing either HSV1-tk (n = 16) or LacZ reporter gene (n = 15) into the inferior wall. Nonmanipulated rats (n = 5) served as further controls. Hearts were excised 2 d later and perfused according to the Langendorff technique with (124)I-FIAU-containing buffer (15 min, followed by 30 min of nonradioactive perfusion). Experiments were performed under baseline conditions and in the presence of thymidine (competitive substrate) or fludarabine (in vitro inhibitor of 5'-nucleotidase). Time-activity curves were acquired by external coincident detectors. The myocardial rate of (124)I-FIAU uptake (K(i)), clearance rate (K(o)), and volume of distribution (V(d) = K(i)/K(o)) were calculated. Subsequently, hearts were subjected to gamma-counting, followed by microtome slicing and autoradiography. RESULTS: The V(d) from Langendorff perfusion significantly correlated with final whole-heart tracer retention (r = 0.88, P = 0.019) and the autoradiographic area of regional myocardial activity (r = 0.89, P = 0.016). HSV1-tk hearts showed higher K(i) and V(d) of (124)I-FIAU compared with that of controls (P < 0.001) and detectable but slower washout compared with that of the LacZ group (P < 0.01). Addition of thymidine to the perfusate inhibited myocardial uptake of (124)I-FIAU by reducing V(d) and K(i) in HSV1-tk and LacZ hearts compared with the baseline. Addition of fludarabine did not result in the expected reduction of washout in HSV1-tk hearts due to inhibition of 5'-nucleotidases (which may dephosphorylate (124)I-FIAU monophosphate). It acted as an uptake inhibitor similar to thymidine, reducing V(d) in HSV1-tk hearts. CONCLUSION: Assessment of specific reporter probe kinetics after regional in vivo reporter gene transfer is feasible using the isolated perfused rat heart preparation. This model allows one to study the effects of pharmacologic interventions and may refine understanding of the reporter probe signal for in vivo imaging. Different nucleoside analogs significantly inhibit (124)I-FIAU uptake, emphasizing the importance of transporter mechanisms for reporter probe kinetics.


Assuntos
Arabinofuranosiluracila/análogos & derivados , Arabinofuranosiluracila/farmacocinética , Perfilação da Expressão Gênica/métodos , Coração/diagnóstico por imagem , Modelos Cardiovasculares , Timidina Quinase/genética , Timidina Quinase/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Adenoviridae/genética , Animais , Simulação por Computador , Estudos de Viabilidade , Técnicas de Transferência de Genes , Genes Reporter , Radioisótopos do Iodo , Cinética , Masculino , Taxa de Depuração Metabólica , Miocárdio/metabolismo , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Proteínas Recombinantes/metabolismo , Transfecção/métodos
14.
J Nucl Med ; 45(11): 1917-23, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15534063

RESUMO

UNLABELLED: PET of reporter gene expression holds promise for noninvasive monitoring of gene therapy. Previously, 2 approaches based on the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) have been successfully applied to the heart. Wild-type HSV1-tk was imaged with (124)I-labeled 2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyl-5-iodouracil (FIAU), and a mutant HSV1-tk (HSV1-sr39tk) was imaged with (18)F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG). The aim of this study was to compare these 2 combinations with regard to specificity, imaging contrast, and reporter probe kinetics using dynamic PET in small and large animals. METHODS: Similar titers of adenovirus-expressing wild-type HSV1-tk (Ad(tk)), mutant HSV1-sr39tk (Ad(sr39tk)), or control genes were directly injected into the myocardium of 24 rats and 8 pigs. Two days later, dynamic PET was performed with a clinical scanner during the 120 min after injection of (124)I-FIAU (Ad(tk) animals and controls) or (18)F-FHBG (Ad(sr39tk) animals and controls). Imaging with (13)N-ammonia was performed to identify cardiac regions of interest. RESULTS: In rats, significant cardiac (124)I-FIAU accumulation occurred in images obtained early (10-30 min) after Ad(tk) injection. Because of tracer washout, however, no difference between Ad(tk)-injected animals and controls was seen in the images obtained later. For (18)F-FHBG, specific myocardial accumulation greater than background levels was detected in Ad(sr39tk)-injected animals at early imaging and, in contrast to (124)I-FIAU accumulation, increased over time until the latest imaging (105-120 min). At maximum, cardiac (18)F-FHBG concentration showed a 4.15 +/- 1.65-fold increase compared with controls (105-120 min), and cardiac (124)I-FIAU concentration reached a maximal increase of 1.34 +/- 0.38-fold compared with controls (10-30 min, P = 0.0014). Global cardiac reporter probe kinetics in rats were confirmed by regional myocardial analysis in pig hearts. Transgene expression was specifically visualized by both approaches. The highest target-to-background ratio of (124)I-FIAU in Ad(tk)-infected pig myocardium was 1.50 +/- 0.20, versus 2.64 +/- 0.49 for (18)F-FHBG in Ad(sr39tk)-infected areas (P = 0.01). In vivo results were confirmed by ex vivo counting and autoradiography. CONCLUSION: Both reporter gene/probe combinations were feasible for noninvasive imaging of cardiac transgene expression in different species. Specific probe kinetics suggest different myocardial handling of pyrimidine (FIAU) and acycloguanosine (FHBG) derivatives. The results favor (18)F-FHBG with mutant HSV1-sr39tk because of continuous accumulation over time and higher imaging contrast.


Assuntos
Arabinofuranosiluracila/análogos & derivados , Perfilação da Expressão Gênica/métodos , Guanina/análogos & derivados , Coração/diagnóstico por imagem , Miocárdio/enzimologia , Timidina Quinase/genética , Timidina Quinase/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Animais , Arabinofuranosiluracila/farmacocinética , Técnicas de Transferência de Genes , Genes Reporter/genética , Terapia Genética/métodos , Guanina/farmacocinética , Radioisótopos do Iodo/farmacocinética , Masculino , Tomografia por Emissão de Pósitrons/métodos , Ratos , Ratos Wistar , Especificidade da Espécie , Suínos , Distribuição Tecidual , Transgenes/genética
15.
J Am Coll Cardiol ; 43(9): 1690-7, 2004 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-15120832

RESUMO

OBJECTIVES: We sought to evaluate the time course of insulin-stimulated myocardial glucose uptake (MGU) in mice that had undergone ablation of glucose transporter-4 (GLUT4). BACKGROUND: The relative importance of GLUT4, the most abundant insulin-responsive glucose transporter, to modulate myocardial glucose metabolism is not well defined. METHODS: Myocardial glucose uptake was assessed at various time points after glucose (1 mg/g) and insulin (8 mU/g) injection in GLUT4-null (G4N) (n = 48) and wild-type (WT) (n = 48) mice with (18)F-2-deoxy-2-fluoro-d-glucose (FDG) using in vivo positron emission tomography (PET), in vitro gamma-counter biodistribution, and isolated, perfused hearts. RESULTS: Baseline assessment with PET imaging showed comparable MGU in G4N (0.66 +/- 0.12) and WT (0.67 +/- 0.11, p = 0.70) mice. Early after insulin injection, WT mice demonstrated a 3.5-fold increase in MGU (2.45 +/- 0.45, p = 0.03), whereas G4N mice presented no increase (1.11 +/- 0.24, p = 0.28). At 60 min, MGU was comparable in G4N (3.19 +/- 0.60) and WT (2.66 +/- 0.47, p = 0.28) mice. In vitro gamma-counter biodistribution evaluation confirmed in G4N mice a lack of MGU increase early after insulin, but a slow response over 120 min. The isolated, perfused hearts of G4N mice during short-term (15 min) insulin stimulation displayed no increase in MGU (0.08 +/- 0.01 ml/g/min), whereas WT mice presented a threefold increase (0.22 +/- 0.01 ml/g/min, p < 0.01). With long-term (60 min) insulin stimulation, similar MGU was found in G4N (0.31 +/- 0.02 ml/g/min) and WT (0.33 +/- 0.04 ml/g per min, p = 0.04) mice. CONCLUSIONS: The G4N mice displayed an increase of MGU in response to insulin similar to that of controls, but with a markedly delayed time response. Our findings underscore the important role of GLUT4 in the rapid adaptive response of myocardial glucose metabolism.


Assuntos
Fluordesoxiglucose F18/metabolismo , Hipoglicemiantes/metabolismo , Insulina/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Miocárdio/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Fluordesoxiglucose F18/administração & dosagem , Transportador de Glucose Tipo 4 , Frequência Cardíaca/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Modelos Cardiovasculares , Proteínas de Transporte de Monossacarídeos/efeitos dos fármacos , Compostos Radiofarmacêuticos/administração & dosagem , Fatores de Tempo , Tomografia Computadorizada de Emissão
16.
Eur Heart J ; 25(7): 551-7, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15120051

RESUMO

AIMS: After acute myocardial infarction (AMI), regional denervation exceeding the scar area has been described. We sought to define the electrophysiologic correlates of denervated, but viable, myocardium by combining scintigraphic imaging with extensive electrocardiographic evaluation in AMI patients treated with early reperfusion therapy. METHODS AND RESULTS: Within 14 days after AMI, 67 consecutive patients underwent radionuclide imaging of myocardial resting perfusion using (201)thallium and of presynaptic sympathetic innervation using (123)I-metaiodobenzylguanidine (MIBG). The mean left ventricular ejection fraction was 58+/-15%. Electrophysiologic studies included evaluation of ventricular repolarisation (resting ECG), depolarisation (signal-averaged ECG), and 24-h Holter monitoring. The perfusion defect, innervation defect, and perfusion/innervation mismatch size of the left ventricle were 14+/-15%, 39+/-22%, and 26+/-16%, respectively. Mismatch was present in 60/67 patients (90%) and correlated with prolonged repolarisation defined by QTc interval (r = 0.40; P < 0.001), and with indexes of delayed depolarisation from signal-averaged ECG (r = -0.32; P = 0.014). Other electrophysiologic parameters did not correlate. During follow-up (4.3+/-1 years) event rates were low, with two cardiac deaths and no severe ventricular arrhythmia causing hospitalisation. CONCLUSIONS: After early reperfusion for myocardial infarction, viable but denervated myocardium is frequent and correlates with slow depolarisation and repolarisation. However, in patients with small infarct size and preserved left ventricular function, these findings seem to have little influence on outcome.


Assuntos
Doenças do Sistema Nervoso Autônomo/fisiopatologia , Coração/inervação , Infarto do Miocárdio/fisiopatologia , Revascularização Miocárdica/métodos , 3-Iodobenzilguanidina , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Estudos Transversais , Eletrocardiografia Ambulatorial , Eletrofisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/cirurgia , Miocárdio , Estudos Prospectivos , Cintilografia , Compostos Radiofarmacêuticos
17.
Mayo Clin Proc ; 79(1): 42-8, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14708947

RESUMO

OBJECTIVES: To determine the frequency and the clinical characteristics of hepatopulmonary syndrome (HPS) in cirrhotic candidates for orthotopic liver transplantation and to identify the major respiratory parameters predictive of the presence of changes in arterial oxygenation. PATIENTS AND METHODS: Patients underwent transthoracic contrast-enhanced echocardiography, pulmonary scintigraphy, pulmonary function test with diffusing capacity of lung for carbon monoxide (DLCO), and measurement of arterial blood gases. RESULTS: Fifty-six patients were studied. Twenty-five patients (45%) presented with intrapulmonary vascular dilatations, but only 9 (16%) fulfilled the criteria for HPS. The clinical or demographic characteristics considered did not differ in the patients with and without HPS. The DLCO value was significantly lower in patients with HPS (P=.01). However, 32 (80%) of 40 patients with low DLCO values did not fulfill the criteria for HPS. An alveolar arterial oxygen gradient (AaPO2) of more than 20 mm Hg showed a higher diagnostic accuracy (91%) in the assessment of HPS than did the DLCO of less than 80% predicted (41%) and the AaPO2 of more than 15 mm Hg (71%). CONCLUSIONS: The AaPO2 proved to be a more reliable index than PaO2 and DLCO for the determination of changes in arterial oxygenation in HPS. The DLCO does not seem to be a good marker for HPS screening. Intrapulmonary vascular dilatations were frequent, even in patients who did not fulfill the criteria for HPS.


Assuntos
Síndrome Hepatopulmonar/diagnóstico , Síndrome Hepatopulmonar/fisiopatologia , Cirrose Hepática/complicações , Pulmão/fisiopatologia , Gasometria , Feminino , Síndrome Hepatopulmonar/sangue , Humanos , Cirrose Hepática/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Capacidade de Difusão Pulmonar/fisiologia
18.
Circulation ; 108(17): 2127-33, 2003 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-14530205

RESUMO

BACKGROUND: Radionuclide imaging of reporter gene expression may be useful for noninvasive monitoring of clinical cardiac gene therapy. Experience until now, however, has been limited to small animals. METHODS AND RESULTS: To evaluate feasibility in a clinically applicable setting, pigs were studied by conventional positron emission tomography (PET) 2 days after regional intramyocardial injection of control adenovirus or adenovirus carrying herpesviral thymidine kinase reporter gene (HSV1-tk). Myocardial blood flow was quantified by use of [13N]ammonia. Subsequently, kinetics of the reporter substrate [124I]-2'-fluoro-2'-deoxy-5-iodo-1-beta-d-arabino-furanosyluracil (FIAU) were assessed over a period of 2 hours. Areas infected with adenovirus expressing HSV1-tk showed significantly elevated FIAU retention during the first 30 minutes after injection. At later times, washout was observed, and retention was not different from that in areas infected with control virus or remote myocardium. Early in vivo FIAU uptake correlated with ex vivo images, autoradiography, and immunohistochemistry for reporter gene product after euthanasia. After intramyocardial injection of both adenoviruses, myocardial blood flow was mildly elevated compared with that in remote areas, consistent with histological signs of regional inflammation. CONCLUSIONS: In vivo quantification of regional myocardial transgene expression is feasible with clinical PET methodology, the radioiodinated reporter probe FIAU, and the HSV1-tk reporter gene. Radioactivity efflux after specific initial uptake was not observed previously in tumor studies, suggesting that tissue-specific differences in nucleoside metabolism influence reporter probe kinetics. By coregistering reporter gene expression with additional biological parameters such as myocardial blood flow, PET allows for noninvasive characterization of the success of cardiac gene transfer along with its functional correlates.


Assuntos
Arabinofuranosiluracila/análogos & derivados , Expressão Gênica , Coração/diagnóstico por imagem , Miocárdio/metabolismo , Tomografia Computadorizada de Emissão , Transgenes , Animais , Arabinofuranosiluracila/farmacocinética , Velocidade do Fluxo Sanguíneo , Circulação Coronária , Estudos de Viabilidade , Técnicas de Transferência de Genes , Genes Reporter , Radioisótopos do Iodo , Modelos Animais , Suínos , Timidina Quinase/genética , Timidina Quinase/metabolismo
19.
Arq. bras. cardiol ; 68(6): 401-405, Jun. 1997.
Artigo em Português | LILACS | ID: lil-320329

RESUMO

PURPOSE: To assess the clinical, angiographic and early follow-up findings of young patients suffering an acute myocardial infarction, in comparison with older patients with infarction, in the thrombolytic era. METHODS: A retrospective analysis of the medical records of 46 patients < 40 years-old (group I) at the time of an acute myocardial infarction was compared with that of 46 older patients, randomly selected, presenting with this syndrome between february, 1991 and february, 1996 (group II). In both groups a comparison was conducted regarding the proportions of gender, risk factors, type of infarction (Q vs non-Q), left ventricular function, coronary anatomy and early mortality (1 month). The medical treatment was comparable for both groups, including the utilization of thrombolytics. RESULTS: The groups were discriminated only by: higher prevalence of smoking, of angiographically normal coronary arteries, and of non-critical (< 75reduction of luminal diameter) coronary stenosis in group I; in the older group a higher proportion of patients had multivessel disease. Although not reaching statistical significance, a trend was observed to a more benign early course of the infarction in the patients less than < 40 years-old. CONCLUSION: The present findings are similar to those described in the pre-thrombolytic era, for young patients suffering an acute myocardial infarction.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Angiografia Coronária , Fibrinolíticos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fumar , Função Ventricular Esquerda
20.
Säo Paulo med. j ; 113(2): 826-34, Mar.-Apr. 1995. ilus, tab
Artigo em Inglês | LILACS | ID: lil-161557

RESUMO

Pathogenesis of chronic Chagas' heart disease may include various disturbances in the coronary circulation, that could be responsible for the myocardial lesions seen in human hearts and in experimental models of the disease. In this paper we critically reviewed the anatomical and functional abnormalities described in chronic chagasic patients, pertaining to the so-called vascular pathogenetic theory of Chagas' disease. The epicardial coronary arteries are usually tree of significant obstructive disease in nonselected groups of chagasic patients examined at autopsy or by coronary angiography. However, chagasic patients who were studied after an episode of acute myocardial infarction, show the same patterns of atherosclerotic coronary artery disease seen in the general nonchagasic population. Studies of chagasic patients with angiographically normal coronary arteries, by several scintigraphy methods, revealed myocardial perfusion abnormalities which may be caused by the microcirculatory derangements described in animals experimentally infected with the T. cruzi. Since hypoperfusion has been detected in regions with normal or mildly impaired wall motion, it is likely that the microvascular disturbances precede and may be a causative mechanism for the subsequent myocardial damage. We speculate that hibernating ventricular areas may occur in chagasic patients, on the basis of the evidence gathered from these studies. Recent investigations of chronic patients with Chagas' disease and chest pain showed attenuation of the vasomotor responses to physiological and pharmacological stimuli, in the epicardial coronary arteries.


Assuntos
Humanos , Animais , Pessoa de Meia-Idade , Circulação Coronária/fisiologia , Cardiomiopatia Chagásica/fisiopatologia , Doença Crônica , Circulação Coronária , Infarto do Miocárdio/patologia , Cardiomiopatia Chagásica/patologia
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